tbuckley/cabot-search huggingface dataset:
Interim results from a phase I/II study of duvelisib PI3Kδγ inhibitor and nivolumab in patients with advanced unresectable melanoma who have progressed on anti-PD1 therapy.
Authors: Jingxiao Jin, Anjali Rohatgi, Andrew Gabrielle, Amy Rose, Melissa Wilson, Tullia C. Bruno, John M. M. Kirkwood
Journal: Journal of Clinical Oncology (2023)

9540 Background: The majority of unresectable melanoma patients eventually progress on first-line checkpoint blockade therapy. Duvelisib is a potent phosphoinositide 3-kinase (PI3K) δ and γ isoform inhibitor approved for relapsed/refractory CLL. PI3Kγ inhibition has been shown to restore anti-PD1 activity in preclinical tumor models through conversion of tumor associated macrophages (TAMs) from an immunosuppressive to a pro-inflammatory state. PI3Kδ inactivation has been associated with impaired T regulatory cell (Treg) function and reduced intratumoral Treg numbers. We report study design and results of a phase I study to evaluate the safety and efficacy of duvelisib and nivolumab in anti-PD1 refractory patients. Methods: Utilizing a modified 3+3 design with escalating doses of duvelisib (15 mg daily, 25 mg daily, and 25 mg BID), patients with unresectable melanoma were treated with nivolumab and duvelisib until unacceptable toxicity or disease progression. Primary endpoints for the phase I portion were maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of duvelisib. Secondary endpoints include early and late toxicities and anti-tumor activity based on RECIST v1.1. Exploratory endpoints were to evaluate dose-dependent changes in the immune cell populations of peripheral blood and tumor tissue with duvelisib and nivolumab. Results: Ten patients have been enrolled (7 at dose level I, 3 at dose level II) with mean age 64. Two patients had BRAF V600E mutation and were previously treated with BRAF/MEK inhibitors. No dose limiting toxicities (DLT) were observed. Grade 3 or higher adverse events (AEs) attributable to study treatment occurred in 4 patients (40%), including G3 neutropenia (10%), G3 diarrhea (10%), G3 vomiting (10%) and G4 hepatitis (20%). Both instances of hepatitis resolved rapidly with 1-2mg/kg of prednisone. In one patient, hepatitis and nausea/vomiting led to discontinuation of treatment. Out of 6 patients who had follow-up imaging, 4 exhibited progressive disease, one stable disease, and one had partial response of 11 months duration. Given the published data on the regulation of macrophages and Tregs by PI3Kδγ inhibitors, we are utilizing multispectral imaging to measure the spatial interactions of key immune cells within the tumor microenvironment (T cells, B cells, and macrophages) in all matched pre-/post-treatment paraffin-embedded tissues, for which results will be presented. Conclusions: The combination of duvelisib and nivolumab was well-tolerated in patients with advanced unresectable melanoma refractory to ICI without DLTs to date at 15 and 25mg daily dosages. Significant anti-tumor activity was noted in one patient. Enrollment at dose level II is ongoing. Clinical trial information: NCT04688658 .
Phase 1 study to determine the safety and efficacy of onvansertib, a novel, oral, PLK1 inhibitor in patients with proliferative chronic myelomonocytic leukemia relapsed/refractory or intolerant to available therapies.
Authors: Kristen McCullough, Abhishek A Mangaonkar, Ashya R. Burgess, Aref Al-Kali, Hassan B. Alkhateeb, Kebede Begna, Naseema Gangat, Susan Michelle Geyer, William J. Hogan, Mark Robert Litzow, Kaaren Reichard, Antoine N Saliba, Mithun Vinod Shah, Alexandra P. Wolanskyj-Spinner, Mrinal Mahesh Patnaik
Journal: Journal of Clinical Oncology (2023)

TPS7089 Background: Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative overlap neoplasm (MDS/MPN) that can be further divided into MD (WBC &lt; 13 x 10 9 /L) and MP (≥13 x 10 9 /L) subtypes. MP-CMML is enriched in RAS pathway mutations ( NRAS, CBL, KRAS, PTPN11 and NF1), has a shorter median survival (19 vs 36 months), has a higher rate of acute myeloid leukemia (AML) transformation (40% vs 10%) and has a unique transcriptomic and epigenetic composition. These RAS pathway mutations promote selective PLK1 overexpression, a mitotic checkpoint kinase. Given the relative inefficacy of hypomethylating agents (HMA) in MP-CMML and previously demonstrated in vitro and in vivo efficacy data for PLK1 inhibition on MP-CMML with RAS pathway mutations, we designed a phase 1 clinical trial testing the safety of onvansertib, a novel, orally bioavailable, PLK1 inhibitor in relapsed/refractory MP-CMML. Methods: This is an investigator-initiated, prospective, open-label, phase I study of onvansertib in MP-CMML relapsed/refractory (RR) or intolerant to existing therapies including HMA and hydroxyurea. The primary endpoint is characterization of safety. Secondary endpoints include efficacy as defined by the 2015 MDS/MPN International Working Group criteria, volumetric spleen response and symptom response via assessment with MPN-SAF-TSS. Inclusion criteria include MP-CMML RR following hydroxyurea or at least 4-cycles of HMA or intolerance of treatment with either, platelets ≥ 20,000/m 3 and Cockcroft-Gault creatinine clearance ≥ 60 mL/min/m 2 . Hydroxyurea may continue for the first 28 days on study. Onvansertib will be given orally on days 1 through 21 of a 28-day cycle with a Bayesian optimal interval design to assess the safety and recommended phase II dose. Exploratory end points include targeting efficacy, impact of PLK1 and KMT2A expression and interactions with ASXL1 and TET2 mutations. Twenty-five patients will be enrolled at Mayo Clinic in Minnesota, with enrollment open since November 2022. Clinical trial information: NCT05549661 .
Genitourinary embryonal rhabdomyosarcoma clinicopathologic determinants of clinical outcomes: Analysis of a pooled database.
Authors: Christopher Graham, Ankita Yelamanchili, Millicent Amankwah, Philip A. Haddad
Journal: Journal of Clinical Oncology (2023)

e23536 Background: Embryonal rhabdomyosarcoma (ERS) refers to malignant soft tissue tumors with phenotypical, histological features of primitive skeletal muscle. ERS commonly involves the head and neck region and genitourinary system. Genitourinary embryonal rhabdomyosarcoma (GUERS) is considered an entity similar to other ERS based on Intergroup Rhabdomyosarcoma Study Group (IRSG) with non-prostate GUERS considered low risk. This study seeks to define other high-risk subtypes in this population. Methods: To study the demographic and molecular characteristics, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 137 cases of GUERS. Kaplan-Meier survival curves, Cox proportional-hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS) and disease-free survival (DFS). Results: 137 patients with confirmed GUERS were identified: median age was 16 and F:M ratio of 1.6. Female reproductive organs (49%), renal and urinary tract (24%), male reproductive organs (23%), and abdomino-pelvis (4%) were involved. Lymph node involvement and metastasis occurred in 11% and 13%, respectively. Staging consisted of stage I (65%), stage II (15%), stage III (8%), and stage IV (12%). Rhabdomyosarcoma clinical groups were mostly IA (41%), IIIA (31%) and IV (13%). Risk groups consisted of low (71%), intermediate (17%), and high (13%). Median OS and DFS were 96 and 42 months, respectively. The primary site of involvement impacted OS, with urinary tract organ involvement having the best median OS, compared to female reproductive organs, male reproductive organs, and abdomino-pelvis involvement (p = 0.01). While primary pelvic disease (p = 0.03), prostate (p = 0.008), and lymph node involvement (p = 0.001) were associated with worse OS, cervix/vaginal involvement tended to have better OS (p = 0.06). Constitutional symptoms (p = 0.0007), obstruction (p = 0.047) and metastases (p = 0.02) were associated with worse OS. Clinical staging system (p = 0.0008), risk groupings (p = 0.06) correlated with OS, but not clinical groupings (p = 0.26). GUERS with vimentin+, CD99- and SMA+ had worse survival (only the latter was statistically significant). Compared to no treatment, RT, CT+/-RT, S+CT+RT were superior with mOS of 2, 6, NR, 96 months, respectively (p &lt; 0.0001). Achieving CR had superior OS (p &lt; 0.0001). OS was not impacted by age, sex, or extent of surgery. Conclusions: Genitourinary embryonal rhabdomyosarcoma is a distinct clinical entity with outcomes worse than other forms of ERS defined by the Clinical Groups of IRSG. Prostate, primary pelvic and obstructive symptoms have worse OS compared to bladder and cervical involvement and we propose their inclusion in the current Clinical Group. This study presents updated clinicopathologic data from a pooled cohort of patients with GUERS.
New insights on oncologist use of genomic testing.
Authors: Mary Lou Smith, Carol B. White, Elda Railey, Stacy W. Gray, David E Gerber
Journal: Journal of Clinical Oncology (2023)

e18741 Background: As the indications and complexity of precision medicine in oncology increase, we sought information about current provider needs and experiences. Methods: In early 2023, we conducted qualitative interviews with medical oncologists who reported treating patients with lung, breast, and/or colorectal cancer. Questions focused on use, concerns, patient communication, resources, and needs related to genomic testing and precision medicine. Results: A total of 24 oncologists were interviewed (50% in practice &gt; 20 years, 71% at community sites, 88% general oncology). Three patterns of tumor genomic testing emerged: (1) Frequent use and an exploratory mindset; (2) measured use, often with a limited set of alterations tested initially, focused on actionable findings; and (3) infrequent use, requiring availability of effective and affordable treatment. Concerns included turnaround time (particularly for lung cancer), workflow and electronic medical record (EMR) non-integration, non-actionable results, cost, and tissue adequacy. Most respondents find test results easy to use, focusing on the first two pages; some use the entire report. Respondents identified problems securing patient access to indicated targeted therapies, particularly oral agents with costly copays requiring substantial staff administrative effort, with the greatest challenges faced by underinsured rather than uninsured patients. Recommendations included improving EMR integration, shortening time-to-result, reflex performance so results are available at initial oncology appointment, standardizing result presentation, and addressing cost issues. In addition, some suggested that centralized collection and analysis of patient outcome data would inform questions of actionability and access. Conclusions: This qualitative work identifies several major challenges practicing oncologists face in delivering precision medicine. Notably, downstream issues related to treatment access may influence decisions regarding tumor genomic profiling. Further investigation of barriers and potential solutions is needed.
Targeting Exportin 1 as treatment for cutaneous squamous cell carcinoma.
Authors: Ricky Rana, Laura A. Hansen
Journal: Journal of Clinical Oncology (2023)

e21564 Background: Cutaneous squamous cell carcinomas (cSCC) are among the most frequent solid cancers in humans and in the U.S., cSCC cases are increasing. Molecular mechanisms transitioning premalignant lesions to cancer are not well characterized. As a result, targeted therapies need to be identified to treat these lesions. Preliminary data shows that Exportin 1 (XPO1) is one of the major proteins regulating nuclear export of proteins, helping to maintain cellular homeostasis. Previous work showed that Exportin 1 modulates the nuclear:cytoplasmic ratio of signaling proteins in skin cancer; resulting in an anti-apoptotic effect by adjusting the nuclear-cytoplasmic balance of pro-survival proteins such as CDC25A and Survivin. XPO1 expression is upregulated in many cancers, thereby affecting the nuclear:cytoplasmic ratio of many pro-survival proteins and enhancing tumorigenesis. This research project was designed to investigate the effects of XPO1 inhibition on cSCC survival. Selinexor is FDA cleared for treatment of multiple myeloma patients. Selinexor is a selective inhibitor of XPO1 regulated nuclear transport causing target molecules to remain within the cell leading to decreased cancer cell growth and decreased cancer cell survival. We hypothesize that inhibiting XPO1 with Selinexor or by CRISPRi genetic knockdown of XPO1 in cSCC cells will reduce proliferation and increase apoptosis in cSCC cells. Methods: Human cSCC cell lines SCC13 and SRB12 were seeded in 96-well plates at 8,000 cells/well density and 3,000 cells/well, respectively. Cells were treated with varying concentrations of Selinexor (0.005mM – 5mM) or DMSO as vehicle control. At 24-hour intervals, cell imaging and Neutral red staining assays were conducted to determine the IC 50 concentration for Selinexor in cSCC cell lines. SCC13 cells stably expressing dCas9-KRAB and a doxycycline-inducible XPO1 guide RNA were used for CRISPRi experiments. Cells were treated with doxycycline daily and apoptosis was assayed by Caspase Glo 3/7 daily for four days. CRIPSRi enabled a doxycycline inducible XPO1 knock down on SCC13 cells allowing us to disrupt the cellular transporter protein XPO1. Results: Selinexor treatment of SRB12 cells resulted in an IC 50 of 1.174 μM and 0.071 μM for SCC13. In contrast, normal human keratinocyte cell lines had higher IC 50 values of 2.18 μM for HaCaT and 5.29 μM for KerCT cells. Apoptosis significantly increased after 72 and 96 hours of XPO1 knock down in SCC13 cells measured by Caspase Glo. Conclusions: These results document how XPO1 inhibition reduces proliferation and is toxic to both normal keratinocytes and cSCC cells. Additionally, cSCC cells had lower IC 50 values for Selinexor, suggesting cSCC may be more sensitive to XPO1 inhibition compared to normal keratinocytes. Further, targeting XPO1 also increases apoptosis in these cells. This data supports the hypothesis that targeting XPO1 may be effective in treating cSCC.
Information and decisional needs of patients (pts) with newly diagnosed advanced cancer in the hospital: A multi-level, mixed-methods study.
Authors: Kevin R Reyes, Paul Wong, Mary Petrofsky, Annie Dai, Alyson Pelayo, Sam Brondfield, Daniel H Kwon
Journal: Journal of Clinical Oncology (2023)

e24177 Background: Pt informed decision-making (IDM) is crucial in cancer care. Little is known about the informational and decisional needs of pts with newly diagnosed advanced cancer in the hospital, for whom unique IDM challenges may exist. Methods: A single-center, mixed-methods study of hospitalized pts with a newly diagnosed, treatment-naïve advanced solid malignancy; their caregivers; and outpatient medical oncologists was conducted from June to November 2022. At discharge, pts were surveyed for cancer type/stage knowledge, treatment knowledge &amp; decisional conflict using the informed subscale &amp; total Decisional Conflict Scale (DCS; scored 0-100, higher = more conflict) respectively, and information timing preferences. Post-discharge semi-structured interviews exploring information/decisional needs were conducted with pts or pt-caregiver dyads. Oncologists were surveyed about the knowledge of the most recent pt they saw who met aforementioned criteria. Quantitative data were analyzed using descriptive statistics and qualitative data using thematic analysis. Results: Of 25 pts approached, 20 (80%) completed the survey. Interviews were halted after 12 pts and 4 caregivers due to saturation. Fifteen (75%) pts knew their cancer type and 10 (50%) their stage. For the DCS, 13 (65%) scored &gt; 37.5, which is linked with decision delay/regret; median informed subscale score was 66.7. Pts reported wanting to be informed as soon as possible (vs. later) about cancer type (90%), stage (85%), treatment options (80%) and prognosis (70%). Interview themes were cancer knowledge, cancer decisions, information needs/uncertainty, barriers/facilitators to information gathering during/post-hospitalization, decision-making barriers/facilitators, locus of control in decision-making, and goals. Of 46 oncologists approached, 32 (70%) completed the survey. Twenty-four (75%) reported that the pt was somewhat/very well-informed about cancer type, 15 (47%) stage, 18 (57%) treatment options and 9 (28%) prognosis. Themes from open-ended questions were inpatient information processing, outpatient care navigation/expectations, and low expectations of pt cancer knowledge. Oncologists recommended pt education, supportive care referrals, and inpatient-outpatient communication at discharge. Conclusions: Pts with an inpatient diagnosis of advanced cancer experience high decisional conflict and are not well-informed about cancer treatment and prognosis. Pts, caregivers, and oncologists identified numerous information/decisional needs and barriers/facilitators. Though some needs were due to barriers unique to hospitalization, pts did not perceive hospitalization as a barrier to IDM. Further studies should explore transitional interventions such as enhanced pt education, supportive care, and standardized, tailored handoffs to the outpatient team.
Subgroup analysis of elderly patients (pts) with diffuse large B-cell lymphoma (DLBCL) in the phase 3 POLARIX study.
Authors: Bei Hu, Patrick Michael Reagan, Laurie Helen Sehn, Jeff Porter Sharman, Mark Hertzberg, Huilai Zhang, Austin Injae Kim, Charles Herbaux, Lysiane Molina, Dai Maruyama, Piotr Smolewski, Frank Stenner, Veronica Craine, Rucha Kothari, Jamie H. Hirata, Deniz Sahin, Matthew Dean Sei Sugidono, Calvin Lee, Herve Tilly
Journal: Journal of Clinical Oncology (2023)

7518 Background: In the Phase 3 POLARIX study (NCT03274492), polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) significantly improved progression-free survival (PFS) compared with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), with a similar safety profile in pts aged 18–80 years with previously untreated DLBCL (Tilly et al. 2022). Combination regimens may be associated with higher rates of toxicity in elderly pts. We report the efficacy and safety of Pola-R-CHP vs R-CHOP in pts aged ≥70 years enrolled in POLARIX. Methods: POLARIX methods were described by Tilly et al. (2022). Pts with previously untreated DLBCL were randomized 1:1 to receive 6 cycles of Pola-R-CHP or R-CHOP, plus 2 cycles of rituximab. This analysis focused on pts aged ≥70 years at enrollment. Results: Overall, 284 pts were analyzed for efficacy (Pola-R-CHP, n=141; R-CHOP, n=143) and 280 pts were analyzed for safety (Pola-R-CHP, n=137; R-CHOP, n=143). Median age was 74 years (range 70–80), and 69.7% had an International Prognostic Index score of 3–5. Most pts in either arm received all 6 doses of polatuzumab vedotin or vincristine (88.3% and 91.6% in the Pola-R-CHP and R-CHOP arms, respectively). At data cutoff (June 28, 2021; median follow-up: 24.2 months), the risk of progression, relapse or death was lower with Pola-R-CHP vs R-CHOP (hazard ratio [HR] 0.64; 95% confidence interval [CI]: 0.41–0.99) (Table). Death by any cause occurred in 14.2% and 19.6% of pts treated with Pola-R-CHP and R-CHOP, respectively. Overall survival (OS) and disease-free survival (DFS) results are presented in the Table. Safety profiles were generally comparable for Pola-R-CHP vs R-CHOP, including rates of Grade 3–5 adverse events (AEs), Grade 5 AEs, serious AEs, peripheral neuropathy (any grade), neutropenia (Grade 3–4), and infection (Grade 3–4) (Table). Conclusions: Pola-R-CHP and R-CHOP demonstrated similar safety profiles in pts aged ≥70 years with previously untreated DLBCL. The risk-benefit profile favored Pola-R-CHP vs R-CHOP. Clinical trial information: NCT03274492 . [Table: see text]
Breast cancer: Global patterns of incidence, mortality, and trends.
Authors: Ephrem Tadele Sedeta, Bilain Jobre, Boris Avezbakiyev
Journal: Journal of Clinical Oncology (2023)

10528 Background: The global burden of cancer incidence and mortality including that of female breast cancer continues to increase largely because of the growth and aging of the population and adoption of western lifestyle behaviors that increase cancer risk. In this study, we summarize the current burden, trends, and survivorship of female breast cancer that account for nearly 12% of the cancer burden worldwide. Methods: Estimates of incidence and mortality in the year 2020 were obtained from Global Cancer Observatory (GLOBOCAN) database. GLOBOCAN provides country-specific estimates of cancer incidence, mortality, and prevalence for 185 countries or territories and 36 cancer types by age group and sex. For US rates, data from Surveillance, Epidemiology, and End Results (SEER) program were assessed. Rates are age-standardized (ASRs) (per 100,000 person-years) using the 1966 Segi-Doll World Standard Population. Geographic variability was assessed using 20 predefined world regions, and the 4-tier Human Development Index (HDI). Finally, we provide a prediction of the future burden of female breast cancer in 2040 based on demographic projections. Results: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide, with an estimated 2.3 million new cancer cases (1 in 4 new cancer cases) and 685,000 cancer deaths (1 in 6 deaths) in 2020. Breast cancer incidence rates varied by nearly 4-fold across WHO areas. The highest incidence rates (per 100,000) were found in Australia/New Zealand (95.5), Western Europe (90.7), and Northern America (89.4), while the lowest rates were in South-Central Asia (26.2), Middle and Eastern Africa (33), and Central America (39.5). In contrast, the highest breast cancer mortality rates were recorded in Melanesia (37.5), Polynesia and Western Africa (22.3), and the Caribbean (18.9), while the lowest rates were found in Eastern Asia (9.8), Central America (10.4), and Australia/New Zealand (12.1), a 2.8-fold difference. In the United States, the age-standardized breast cancer incidence rate (per 100,000) increased from 106 (1975) to 142 (1999), decreased to 128 (2004), and then slowly increased to 137 (per 100,000) in 2019. Similar broad temporal trend patterns were observed in other western countries. Incidence rates are rising in South America, Africa, and Asia where rates were historically low. Worldwide, an estimated 2,964,197 new female breast cancer cases are projected to occur in 2040, a 31% increase from the corresponding 2,260,127 cases in 2020. Conclusions: There is significant variation in female breast cancer incidence and mortality rates worldwide. Breast cancer incidence is increasing at different rates in various regions of the world. Mortality rates in many high HDI countries have been on the decline, in contrast to increasing rates in low HDI countries. This study also shows a substantial increase in new breast cancer diagnoses over the next two decades.